Patent GB-941564-A (GB)
Title: Substituted 3, 3, 6-trimethyl heptanes and the preparation of dihydrochrysanthemic acid compounds therefrom
Filed: 1959-12-04
Abstract: The invention comprises compounds of the general formula <FORM:0941564/C2/1> where X represents a halogen atom, preferably chlorine or bromine, or an organic sulphonyloxy group and Y represents a -CH2CN group, or X represents a -CH2COOR group (where R represents a lower alkyl group containing up to 6 carbon atoms) and Y represents a halogen atom.  The first class of compounds are prepared from compounds of the general formula (III) <FORM:0941564/C2/2> where Y1 is a -CH2CN group and X1 is a hydroxyl group by replacing the hydroxyl group by a halogen atom or an organic sulphonyloxy group by known methods, for example by reacting with thionyl chloride, or with a sulphonyl halide in the presence of an organic base.  The second class of compounds are prepared by treating a lactone of the formula <FORM:0941564/C2/3> either with a hydrogen halide in an alcohol ROH, or with thionyl chloride and subsequently with a hydrogen halide in an alcohol ROH.  Both classes of compounds are converted into derivatives of (dl) trans-dihydrochrysanthemic acid by ring-closing with an alkaline reagent, preferably, by heating with an alkali metal hydride, amide or alkoxide in an inert solvent. The product, which has the formula <FORM:0941564/C2/4> where A represents a -CN or COOR group, can be converted into (dl) trans-dihydrochrysanthemic acid or a salt thereof by hydrolysis. Starting materials having formula III wherein X is hydroxyl and Y is -CH2CN, are prepared by condensing isovaleraldehyde with a compound (CH3)2C=C(CN)Q where Q is a hydrogen atom or a carboxylic ester group to form a ketone (CH3)2CH. CH2. CO. C(CH3)2CH2CN (after hydrolysis and decarboxylation when Q is a carboxylic ester group), and reducing the ketone to the desired carbinol e.g., with lithium aluminium tributoxy hydride or potassium boro-hydride or by the Meerwein-Ponndorf method. The lactone defined above is prepared by condensing acetaldehyde with an ester (CH3)CH-CH2CH=C(COOR)2 in the presence of an acyl peroxide, converting the resulting ester (CH3)2 CH-CH2-CH(CO-CH3)-CH(COOR)2 into the compound (CH3)2CH-CH2-CH(CO-CH3)CH2 -COOR, for example, by hydrolysis with methanolic KOH followed by acidification and esterification with ethanol, and finally, reacting the said compound with CH3MgI to form the desired lactone. In examples, (1) isovaleraldehyde is condensed with ethyl isopropylidenecyanacetate in the presence of benzoyl peroxide yielding ethyl 2-cyano-3,3,6-trimethyl-4-oxoheptanoate which is hydrolysed in aqueous ethanolic KOH and the product decarboxylated at 120 DEG C., in vacuo to give 3,3,6-trimethyl-4-oxoheptanonitrile, which is reduced to the 4-hydroxyheptanonitrile; the nitrile is reacted with toluene-p-sulphonyl chloride in the presence of pyridine and the resulting toluene sulphonic ester of the nitrile is heated with sodamide in dimethylformamide to yield (dl) trans-dihydrochrysanthemo nitrile; (2) isovaleraldehyde is condensed with dimethyl-acrylonitrile, the resulting trimethyl-oxoheptanonitrile is reduced, the so-formed hydroxynitrile is esterified with methyl-sulphonyl chloride and the resulting ester is converted into dihydrochrysanthemonitrile as in (1); (3) the dihydrochrysanthemonitrile is heated with KOH in glycol and the product worked up to give the free (dl) trans-dihydrochrysanthemic acid; (4) acetaldehyde is condensed with ethyl isovalerylidenemalonate yielding ethyl 5-methyl-3-acetyl-2-carbethoxy-hexanoate which is saponified and decarboxylated by heating in methanolic KOH; the resulting 5-methyl-3-acetyl hexanoic acid is converted into its ethyl ester which is cyclised into the above described lactone with the aid of CH3MgI and the latter is reacted with ethanolic HCl yielding a chloroester which is treated with sodium amoxide to give ethyl (dl) trans-dihydrochrysanthemate; the ester on treatment with KOH in methanol and acidifying, yields the free acid; (5) the lactone obtained in (4) is refluxed with thionyl chloride in benzene, and the resulting solution is poured into ethanolic HCl and the so-formed chloro-ester is cyclised as in (4).